There is increasing concern for the possible oncogenic potential of agents used to treat cancer. To some extent, concern about the production of a second malignancy is the price of success. After all, the patient must be a long-term survivor, with the first malignancy cured - or least controlled, before the possibility of a treatment-induced second malignancy becomes a problem. Hyperthermia is one of the few agents used to treat cancer (other than the surgeon's knife) which does not of itself induce oncogenic transformations; by comparison, radiation is a weak oncogenic agent, while some chemotherapy agents are relatively potent. The purpose of the present investigation is to determine whether hyperthermia, used to potentiate chemotherapy, enhances the transformation incidence to the same extent as it enhances cell lethality. To be specific: For a given level of cell killing, does thermochemotherapy produce an equally elevated level of oncogenic transformation, or can a sequence be found for some chemetherapy agents where cytotoxicity is enhanced without a concomitant increase in oncogenicity? This has proved to be the case for x-rays, but it is not known for chemical agents. Three chemotherapy agents will be tested in the first instance, namely Bleomycin, Melphalan and Cis-platinum. Oncogenic transformation will be assayed in vitro using an established line of mouse fibroblasts, designated C3H/10T-1/2 cells. These cells show contact inhibition, and stop dividing when grown to confluence. However, following treatment with oncogenic agents, such as radiation and chemicals, foci are observed at low incidence in which cells lose contact inhibition, become piled up and densely stained, and show a characteristic morphology with a criss-cross pattern at the periphery of the colony. These cells produce fibrosarcomas when injected into suitably prepared animals. There is a good correlation between transformation in vitro identified by a changed morphology and carcinogenesis in vivo.